Synergistic catalysis in the sonogashira coupling reaction: Quantitative kinetic investigation of transmetalation

Article abstract of DOI:10.1002/anie.201207970

Rate-limiting: The transmetalation step of the Sonogashira coupling reaction has been established as the rate-limiting step. This cross-coupling has been demonstrated to be a Pd-catalyzed and Cu-catalyzed synergistic process, which exhibits a first-order

Full text of DOI:10.1002/anie.201207970

Angewandte
Chemie
DOI: 10.1002/anie.201207970
Cross-Coupling
Synergistic Catalysis in the Sonogashira Coupling Reaction:
Quantitative Kinetic Investigation of Transmetalation**
Chuan He, Jie Ke, Huan Xu, and Aiwen Lei*
À
The formation of a Csp Csp bond is the key step for the
coupling reaction has been performed by using in situ
measurements. Meanwhile, palladium and copper are dem-
onstrated to be the synergistic catalysts in the Sonogashira
coupling reaction.
Owing to the interest in the mechanism of the Sonoga-
shira coupling reaction, we firstly used some classic conditions
for the coupling of aryl iodide 1a and phenylacetylene 2a
monitored by in situ IR spectroscopy. The results are
compiled in Table 1 and Figure 1.
The reactions proceeded smoothly and gave even quanti-
tative yields under these typical conditions (Table 1,
entries 1–4). However, the kinetic behaviors were distinct.
2
construction of arylalkyne and conjugated enyne moieties,
which widely exist in natural products, medicine molecules,
agrochemicals, and organic functional materials.[1] The Sono-
gashira coupling between aryl or vinyl halides and terminal
alkynes is one of the most efficient tools to furnish the above-
mentioned motif. This named reaction is well-known as a Pd-
catalyzed process, and its scope and parameters such as Pd
precursors, ligands, additives etc. have been extensively
studied during the past 40 years.[1b–d,h,j–m] However, scarce
examples regarding the detailed reaction mechanism have
been reported.[2] And to our knowledge, no quantitative
kinetic information about the transmetalation step of the
Sonogashira coupling has been obtained by in situ measure-
ments has been reported to date.
Table 1: Kinetic investigation of the Sonogashira coupling reaction.[a]
The general catalytic cycle of transition-metal-catalyzed
cross-coupling reactions, such as Negishi coupling, Suzuki
coupling, Stille coupling, and Sonogashira coupling etc.
includes three elementary steps: oxidative addition, trans-
metalation, and reductive elimination.[1h,j,o] Although numer-
ous efforts have been focused on the methodology develop-
ment during the past three decades, very few have been
devoted to the kinetic investigations, especially for the
transmetalation step.[3] Espinet et al. have studied the organo-
tin-reagents-related transmetalation step of the Stille cou-
pling in the past few years.[3h–l] Recently, transmetalations of
the organozinc reagents in the Negishi coupling were also
investigated.[3m–o,4] Herein, we communicate our direct kinetic
investigation of a Sonogashira coupling reaction by using
in situ IR spectroscopy. In this reaction, transmetalation is
assigned as the rate-limiting step. The quantitative kinetic
Entry
[Pd]
Base and solvent
T
Yield [%][b]
1
2
3
4
5
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[Pd(PPh3)4]
[Pd(PPh3)4]
Et3N
258C
258C
258C
08C
quant.
quant.
quant.
quant.
20
iPr2NH
iPr2NH
iPr2NH
Et3N
[Pd(PPh3)4]
08C
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), [Pd] (1 mol%),
and CuI (2 mol%) in 5 mL of solvent. [b] Determined by GC with
naphthalene as the internal standard.
measurement of the transmetalation step for the Csp–Csp
2
[*] C. He, J. Ke, H. Xu, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, 430072 (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Figure 1. Kinetic profiles of Table 1 monitored by in situ IR spectrosco-
py. a) [PdCl2(PPh3)2] was used as the catalyst precursor. b) [Pd(PPh3)4]
was used as the catalyst precursor.
354 Fenglin Lu, Shanghai, 200032 (P.R. China)
[**] This work was supported by the “973” Project from the MOST of
China (2011CB808600) and the National Natural Science Founda-
tion of China (21025206, 20832003, 20972118, 20972119). We also
thank “the Fundamental Research Funds for the Central Univer-
sities”, Program for New Century Excellent Talents in University
(NCET) and the Program for Changjiang Scholars and Innovative
Research Team in University (IRT1030).
The reaction using iPr2NH was much faster and more
effective than that using Et3N (Figure 1a). Meanwhile, the
inductive periods existed in both reactions. It could be
rationalized that the PdII species should be reduced to the
active Pd0 catalyst at the beginning of the reaction.[5] When
[Pd0(PPh3)4] was employed instead of [PdCl2(PPh3)2], the
inductive period disappeared, and the reaction proceeded
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207970.
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much faster even at 08C in iPr2NH (Figure 1b, entries 3 and
4). However, Et3N was less effective under the same
conditions (Figure 1b, entry 5). It was noteworthy that these
three Pd0-catalyzed reactions all exhibited zero-order kinet-
ics, which apparently indicated that reductive elimination
might be the rate-limiting step in this transformation.
Detailed kinetic investigations of the Sonogashira cou-
pling reactions were further performed in iPr2NH at 08C
[Eq. (1) in Figure 2]. In Figure 2a the kinetic profiles at
varying initial concentrations of 1a are shown. The nearly
identical initial rates indicated that this reaction was zero-
order dependent on c(1a). This result could rule out the
oxidative addition of ArI with the Pd catalyst as the rate-
limiting step. Meanwhile, Figure 2b showed the kinetic plots
of the reactions when c(2a) was varied. The almost perfectly
overlaying initial kinetic rates revealed that this Sonogashira
coupling was also independent on the concentration of the
terminal alkyne c(2a). Furthermore, kinetic measurements
with different concentrations of the [Pd] catalyst were
investigated. A linear relationship was observed in Figure 2c
when plotting the initial rate versus c([Pd]). This result
suggested that the reaction was first-order dependent on the
concentration of the Pd catalyst in the tested Pd concen-
tration range. Thus far, all the above kinetic observations
suggested that reductive elimination might be the rate-
limiting step.
However, when we tried to further reveal the relationship
between the electronic effect of substituent and rate-limiting
step, we faced a puzzle. As shown in Figure 3a, the more
electron-withdrawing the substituent on the electrophile ArI
1 was, the faster the reaction proceeded. This result was
unanticipated. The reversed trend was observed when the
substituents on the nucleophile alkynes 2 were investigated
(Figure 4a). The more electron-withdrawing group the alkyne
had, the slower the reaction occurred. Although the elec-
Figure 3. a) Kinetic profiles of different aryl iodides 1 monitored by
in situ IR spectroscopy. b) The Hammett correlation plot. The rate
constant k was obtained by fitting the linear plot of c(3) versus time.
Plotting log(k/k0) versus the substituent constant sp for these sub-
strates gave a linear relation (correlation coefficient r2 =0.96, positive
slope 1=1.29).
bond. At the beginning, we assumed if the reductive
elimination is rate-limiting, the electronic effects on varying
the substituents of only one, the electrophile or the nucleo-
phile, should follow the same trend when the other is
constant. The results of the experiments shown in Figures 3a
and 4a were just different from the speculation. This puzzle
enforced us to reappraise the catalytic cycle of the Sonoga-
shira coupling reaction.
In fact, different from other Pd-catalyzed cross-coupling
reactions, the Sonogashira coupling usually also required Cu
salt as a cocatalyst.[7] In the above-mentioned kinetic experi-
ments, CuI (2 mol%) was also employed. Two synergistic
catalytic cycles are generally proposed for the Sonogashira
coupling reaction (Scheme 1).[1h,j,l,m] For the Pd-catalyzed
Sonogashira coupling, one usually considers that ArI is the
electrophile, and the terminal alkyne is the nucleophile. In
this way, when the kinetic data showed the reaction was
independent on both c(electrophile ArI) and c(nucleophile
alkyne), reductive elimination
À
tronic effects on the reductive elimination to form a C C
bond had been revealed to some extent,[6] there are rare
À
examples for the reductive elimination to form a Csp Csp
2
as the rate-limiting step could
be easily envisioned. However,
a careful analysis of the cata-
lytic cycle reveals the terminal
alkyne is not the direct nucleo-
phile of the Pd-catalyzed cycle!
The proposed copper–acetylide
is the nucleophile for the Pd-
catalyzed cycle, and is also the
catalytic species for the Cu-
catalyzed cycle.[8] Therefore,
the zero-order kinetic depend-
ences of c(ArI) and c(alkyne)
cannot suggest reductive elim-
ination is the rate-limiting step
Figure 2. a) Kinetic profiles of different initial concentrations of 1a (from 0.2m to 0.4m). Reaction
conditions: 2a (0.22m), [Pd(PPh3)4] (0.002m), CuI (0.004m), carried out in iPr2NH (5 mL) at 08C.
b) Kinetic profiles of different initial concentrations of 2a (from 0.22m to 0.4m). Reaction conditions: 1a
(0.20m), [Pd(PPh3)4] (0.002m), CuI (0.004m), carried out in iPr2NH (5 mL) at 08C. c) Kinetic profiles of
different [Pd(PPh3)4] loadings (from 0.25 mol% to 1.0 mol%) with CuI (0.004m), 1a (0.20m), and 2a
(0.22m), carried out in iPr2NH (5 mL) at 08C. Reactions were monitored by in situ IR spectroscopy.
in this case. The rate-limiting
transmetalation of copper–ace-
tylide with the R1PdX complex
A could also lead to the zero-
order kinetic behavior.
2
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Figure 5. Kinetic profiles of different CuI loadings (from 1.0 mol% to
4.0 mol%) with [Pd(PPh3)4] (0.002m), 1a (0.20m), and 2a (0.22m),
carried out in iPr2NH (5 mL) at 08C. Reactions were monitored by
in situ IR spectroscopy.
Figure 4. a) Kinetic profiles of different terminal aryl alkynes 2 moni-
tored by in situ IR spectroscopy. b) The Hammett correlation plot. The
rate constant k was obtained by fitting linear plot of c(3) versus time.
Plotting log(k/k0) versus sp for these substrates gave a linear relation
(correlation coefficient r2 =0.94, negative slope 1=À1.65).
first time that a first-order kinetic dependence on the Cu salt
is determined in a “live” Sonogashira cross-coupling. Notably,
the first-order kinetic dependence on both palladium catalyst
and copper catalyst established the synergistic catalysis in this
Sonogashira coupling reaction. Moreover, if transmetalation
is rate-limiting, the catalyst resting states should be PdII
complex A and copper–acetylide respectively. The 31P NMR
experiments confirmed that the PdII complex A was indeed
the resting state in this reaction (see Figure S11 in the
Supporting Information).
Moreover, after it was confirmed that transmetalation is
the rate-limiting step, we believed that this model Sonoga-
shira coupling reaction might provide a good opportunity to
quantitatively measure the rate constant and activation
À
enthalpy for the transmetalation of the Csp Csp bond
formation. The model kinetic reaction of 1a and 2a was
2
Scheme 1. Catalytic cycle of the Sonogashira coupling reaction that is
synergistically catalyzed by Pd and Cu. OA=oxidative addition,
TM=transmetalation, RE=reductive elimination.
carried out at different temperatures (Figure 6). As trans-
When assuming transmetalation is the rate-limiting step in
this Sonogashira cross-coupling, the kinetics and electronic
effect of the substituent then can be fit well. The Hammett
correlation plots in Figures 3b and 4b revealed insights into
the transmetalation of the copper–acetylide with [ArPdILn].
The positive 1 (1.29) value indicates that the [ArPdILn] acts as
an electrophile (Figure 3b), while the negative 1 (À1.65)
value indicates that the copper–acetylide acts as a nucleophile
(Figure 4b). The electron-withdrawing substituent on ArI
1 would enhance the electrophilicity of PdII complex A, which
would be more easily attacked by the nucleophile copper–
acetylide. Meanwhile, the electron-donating substituent on
arylacetylenes 2 would enhance the nucleophilicity of the
copper–acetylide, which would more easily react with PdII
complex A.
What is the rate-limiting step, reductive elimination or
transmetalation? From the speculated catalytic cycle for
synergistic catalysis in Scheme 1, the dependence of the
kinetic behavior on the Cu salt could give the answer. If
reductive elimination is the rate-limiting step, the dependence
of the kinetic behavior on the Cu salt should be zero-order. If
transmetalation is the rate-limiting step, the kinetic depend-
ence on the Cu salt should be first-order.
Figure 6. Kinetic profiles of the reaction of 1a with 2a to 3a at
different temperatures monitored by in situ IR spectroscopy. Condi-
tions: [Pd(PPh3)4] (1 mol%), CuI (2 mol%), iPr2NH, N2.
metalation is the rate-limiting step and the reaction shows
first-order dependence on both c([Pd(PPh3)4]) and c(CuI),
the transmetalation rate constant k = kobs/[c([Pd(PPh3)4])x
À
c(CuI)]. The transmetalation rate constants for the Csp Csp
2
bond formation were obtained from 587.5mÀ1 sÀ1 at 258C to
31.0mÀ1 sÀ1 at À258C (Figure 6). The plot of ln(k/T) versus 1/T
allowed us to calculate the activation parameters, and the
activation enthalpy was determined as 8.5 kcalmolÀ1 (see
Figure S10 in the Supporting Information). Compared to the
À
oxidative coupling of arylzinc reagents for Csp Csp bond
2
2
formation,[4] the value of activation enthalpy in this case is
lower. It means that this type of Sonogashira coupling
reaction, which is synergistically catalyzed by palladium and
copper, is a facile transformation.
In fact, the first-order kinetic dependence on the concen-
tration of Cu salt indeed indicated that transmetalation is the
rate-limiting step (Figure 5).[9] To our knowledge, this is the
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In conclusion, the transmetalation step of the Sonogashira
coupling reaction is established as the rate-limiting step. This
well-known cross-coupling is demonstrated to be a Pd-
catalyzed and Cu-catalyzed synergistic process, which exhibits
a first-order kinetic dependence on the [Pd] and [Cu]
catalysts, respectively. To our knowledge, it is also the first
quantitative in situ measurement of the kinetics of the
À
transmetalation step for a Csp Csp bond formation from
a catalytic reaction. The activation enthalpy is determined as
2
8.5 kcalmolÀ1 for the transmetalation. We believe that these
quantitative investigations provide a useful insight into the
nature of catalytic reactions, which will be helpful for the
understanding of the mechanisms and for the synthetic
applications.
Experimental Section
General procedure: A three-necked reaction vessel was fitted with
a magnetic stirring bar. The IR probe was inserted through an adapter
into the middle neck; the other two necks were capped by septa for
injections and a nitrogen line. CuI (0.02 mmol) was added, and the
reactor was allowed to be vacuumed and purged with nitrogen for
three times. After that iPr2NH (5.0 mL), phenylacetylene 2a
(1.1 mmol), and ethyl-4-iodobenzoate 1a (1.0 mmol) were added in
by using syringes. The mixture was allowed to stir at 08C. Then the
data collection was started, followed by addition of [Pd(PPh3)4]
(0.01 mmol) to start the reaction. In situ IR spectra were recorded
over the course of the reaction.
Received: October 3, 2012
Published online: && &&, &&&&
Keywords: cross-coupling · kinetics · reaction mechanisms ·
.
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4
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Communications
Cross-Coupling
Rate-limiting: The transmetalation step
of the Sonogashira coupling reaction is
established as the rate-limiting step. This
cross-coupling is demonstrated to be
a Pd-catalyzed and Cu-catalyzed syner-
gistic process, which exhibits a first-order
kinetic dependence on both the [Pd] and
[Cu] catalysts.
C. He, J. Ke, H. Xu,
A. Lei*
&&&& — &&&&
Synergistic Catalysis in the Sonogashira
Coupling Reaction: Quantitative Kinetic
Investigation of Transmetalation
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